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Abstract:

1 The mechanisms of action of antagonists of the γ-aminobutyric acid C (GABA C) receptor picrotoxin, quercetin and pregnanolone were studied. 2 Ionic currents (chloride), mediated through human homomeric GABA ρ1 receptors expressed in Xenopus oocytes, were recorded by two-electrode voltage clamp. 3 Dose-response (D-R) curves and kinetic measurements of GABA ρ1 currents were carried out in the presence or absence of antagonists. Use-dependent actions were also evaluated. 4 Picrotoxin, quercetin and pregnanolone exerted noncompetitive actions. 5 IC 50 values measured at the EC 50 for GABA (1 μM) were as follows: picrotoxin 0.6±0.1 μM (Hill coefficient n = 1.0±0.2); quercetin 4.4±0.4 μM (n = 1.5±0.2); pregnanolone 2.1±0. 5 μM (n = 0.8±0.1). 6 These antagonists produced changes only in the slope of the linear current-voltage relationships, which was indicative of voltage-independent effects. 7 The effect of picrotoxin on GABA ρ1 currents was use-dependent, strongly relied on agonist concentration and showed a slow onset and offset. The mechanism was compatible with an allosteric inhibition and receptor activation was a prerequisite for antagonism. 8 The effect of quercetin was use-independent, showed relatively fast onset and offset, and resulted in a slowed time course of the GABA-evoked currents. 9 The effect of pregnanolone was use-independent, presented fast onset and a very slow washout, and did not affect current activation. 10 All the antagonists accelerated the time course of deactivation of the GABA ρ1 currents.

Registro:

Documento: Artículo
Título:Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA ρ1 receptor
Autor:Goutman, J.D.; Calvo, D.J.
Filiación:Departamento de Fisiología, Biología Molecular y Celular, Universidad de Buenos Aires, Vuelta de Obligado 2490, (1428) Ciudad de Buenos Aires, Argentina
Palabras clave:Chloride channels; Flavonoids; GABA; GABA c receptors; Picrotoxin; Retina; Steroids; Xenopus oocytes; 4 aminobutyric acid C receptor blocking agent; 4 aminobutyric acid receptor; 4 aminobutyric acid receptor rho1; eltanolone; picrotoxin; quercetin; unclassified drug; allosterism; animal cell; article; binding competition; binding kinetics; chloride current; concentration response; controlled study; dose response; dose time effect relation; drug activity; drug mechanism; drug receptor binding; electric potential; electrode; human; human cell; IC 50; inhibition kinetics; nonhuman; oocyte; priority journal; protein expression; receptor blocking; receptor upregulation; voltage clamp; Xenopus; Animals; DNA, Complementary; Dose-Response Relationship, Drug; Electrophysiology; Evoked Potentials; GABA Antagonists; gamma-Aminobutyric Acid; Humans; Kinetics; Oocytes; Patch-Clamp Techniques; Picrotoxin; Pregnanolone; Quercetin; Receptors, GABA-B; Recombinant Proteins; Xenopus laevis
Año:2004
Volumen:141
Número:4
Página de inicio:717
Página de fin:727
DOI: http://dx.doi.org/10.1038/sj.bjp.0705657
Título revista:British Journal of Pharmacology
Título revista abreviado:Br. J. Pharmacol.
ISSN:00071188
CODEN:BJPCB
CAS:eltanolone, 128-20-1; picrotoxin, 124-87-8; quercetin, 117-39-5; DNA, Complementary; GABA Antagonists; GABA type B receptor, subunit 1; Picrotoxin, 124-87-8; Pregnanolone, 128-20-1; Quercetin, 117-39-5; Receptors, GABA-B; Recombinant Proteins; gamma-Aminobutyric Acid, 56-12-2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00071188_v141_n4_p717_Goutman

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Citas:

---------- APA ----------
Goutman, J.D. & Calvo, D.J. (2004) . Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA ρ1 receptor. British Journal of Pharmacology, 141(4), 717-727.
http://dx.doi.org/10.1038/sj.bjp.0705657
---------- CHICAGO ----------
Goutman, J.D., Calvo, D.J. "Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA ρ1 receptor" . British Journal of Pharmacology 141, no. 4 (2004) : 717-727.
http://dx.doi.org/10.1038/sj.bjp.0705657
---------- MLA ----------
Goutman, J.D., Calvo, D.J. "Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA ρ1 receptor" . British Journal of Pharmacology, vol. 141, no. 4, 2004, pp. 717-727.
http://dx.doi.org/10.1038/sj.bjp.0705657
---------- VANCOUVER ----------
Goutman, J.D., Calvo, D.J. Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABA ρ1 receptor. Br. J. Pharmacol. 2004;141(4):717-727.
http://dx.doi.org/10.1038/sj.bjp.0705657